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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: Gene expression profiles of cSAM leukemia cells with Setdb1 depletion [RNA-seq]

GSE266097 Mus musculus Expression profiling by high throughput sequencing 6 samples Submitted 2024/08/03 Platform GPL28330
Summary
Monocytic acute myeloid leukemia (AML) responds poorly to current treatments, including venetoclax-based therapy. We conducted in vivo and in vitro CRISPR/Cas9 library screenings using a mouse monocytic AML model, and identified SETDB1 and its binding partners (ATF7IP and TRIM33) as crucial tumor promoters in vivo. The growth-inhibitory effect of Setdb1 depletion in vivo was mainly dependent on NK cell-mediated cytotoxicity. Mechanistically, SETDB1 depletion upregulated interferon-stimulated genes and NKG2D ligands through demethylation of histone H3 Lys9 at the monocyte-specific enhancer regions, thereby enhancing their immunogenicity to NK cells and intrinsic apoptosis. Importantly, these effects were not observed in non-monocytic leukemia cells. We also identified the expression of MNDA and its murine counterpart Ifi203 as biomarkers to predict the sensitivity of each AML to SETDB1 depletion. Our study highlights the critical and selective role of SETDB1 in monocytic AML and underscores its potential as a therapeutic target for current unmet needs.
Published in
SETDB1 suppresses NK cell-mediated immunosurveillance in acute myeloid leukemia with granulo-monocytic differentiation
Chang YH, Yamamoto K, Fujino T et al. · Cell reports 2024 · PMID 39096901 · doi:10.1016/j.celrep.2024.114536
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Also filed as BioProject PRJNA1105879 and SRA study SRP504579. Searching any of these in the dataset finder brings you back here.

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